Gray platelet syndrome: proinflammatory megakaryocytes and α-granule loss cause myelofibrosis and confer metastasis resistance in mice
Gray platelet syndrome: proinflammatory megakaryocytes and α-granule loss cause myelofibrosis and confer metastasis resistance in mice
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DOI：
10.1182/blood-2014-04-566760
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发表时间：
2014-12-04
期刊：
影响因子：
20.3
通讯作者：
Ghevaert, Cedric
中科院分区：
文献类型：
--
作者：
Guerrero, Jose A.;Bennett, Cavan;Ghevaert, Cedric
NBEAL2 编码一种多结构域支架蛋白，在人血小板颗粒个体发育中具有假定的作用。 NBEAL2 突变是灰血小板综合征 (GPS) 的基础，这是一种罕见的遗传性出血性疾病，其特征是血小板内缺乏 α 颗粒和进行性骨髓纤维化。我们在这里提出了一种新的 Nbeal2(-/-) 小鼠 GPS 模型，并证明α颗粒的缺乏是由于血小板/成熟巨核细胞 (MK) 的损失，而不是由于最初的形成受损。我们发现，Nbeal2 的缺乏赋予骨髓 MK 促炎表型，这与 α 颗粒蛋白质的损失相结合，驱动了骨髓纤维化的发展。此外，我们证明α-颗粒缺乏会损害血小板功能，超出其纯粹的止血作用，并且 Nbeal2 缺乏对癌症转移具有保护作用。
NBEAL2 encodes a multidomain scaffolding protein with a putative role in granule ontogeny in human platelets. Mutations in NBEAL2 underlie gray platelet syndrome (GPS), a rare inherited bleeding disorder characterized by a lack of alpha-granules within blood platelets and progressive bone marrow fibrosis. We present here a novel Nbeal2(-/-) murine model of GPS and demonstrate that the lack of alpha-granules is due to their loss from platelets/mature megakaryocytes (MKs), and not by initial impaired formation. We show that the lack of Nbeal2 confers a proinflammatory phenotype to the bone marrow MKs, which in combination with the loss of proteins from alpha-granules drives the development of bone marrow fibrosis. In addition, we demonstrate that alpha-granule deficiency impairs platelet function beyond their purely hemostatic role and that Nbeal2 deficiency has a protective effect against cancer metastasis.